DESCRIPTION (provided by applicant: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death and affects more than 11 million Americans. Current techniques for assessing COPD have fundamental limitations, and therefore an urgent need exists for an improved method for accurately staging and monitoring progression of COPD. Diffusion MRI based on hyperpolarized (HP) noble gases has shown great promise for non-invasively evaluating COPD. However, nearly all diffusion MRI research has been performed using 3He, which, due to recent escalation in demand, is now in very limited supply for medical imaging. Increases in 129Xe polarization from recent technical advances now make 129Xe a viable alternative for HP-gas MR imaging. Nonetheless, research with HP 129Xe lags significantly behind that for HP 3He. In particular, acquisition parameters that have served well for HP 3He diffusion MRI cannot be directly translated for use with 129Xe because of its much lower diffusivity and higher biological solubility compared to 3He. As a result, before HP 129Xe diffusion MRI can be used to investigate lung diseases, the imaging parameters need to be optimized and validated. The purpose of the proposed work is to use computer simulations as a guide for optimizing HP 129Xe diffusion MRI acquisition parameters for the evaluation of COPD at the two time scales (short-time scale: ~ms; long-time scale: ~s) that have proven useful with HP 3He, and to perform a small proof-of-concept trial comparing optimized HP 129Xe diffusion MRI with optimized HP 3He diffusion MRI, computed tomography (CT) and pulmonary function tests (PFTs). To determine appropriate parameter spaces for optimization, computer simulations will be performed based on the alveolar-sleeve model for short-time scale diffusion (Specific Aim 1) and on a multi-branch-point model of the human acini for long-time scale diffusion (Specific Aim 2). For both Specific Aims 1 and 2, diffusion values will then be measured at multiple diffusion times and b values in a single breath hold in 10 healthy subjects and 10 subjects with COPD. The experimental results of Specific Aims 1 and 2 will then be combined with realistic imaging conditions to predict optimum imaging parameters for both time scales. Finally, a small proof-of-concept clinical trial will be performed using the optimized parameters to investigate the performance of HP 129Xe diffusion MRI for COPD (Specific Aim 3). Regional HP 129Xe and 3He diffusion will be measured at both time scales in 10 healthy subjects and 30 subjects with COPD (10 at Gold Stage 1, 10 at Gold Stage 2, 10 at Gold Stage 3-4). The resulting 129Xe diffusion maps will be registered with 3He diffusion maps and chest CT images to permit evaluation of the concordance of the structural changes in COPD as detected by MRI and CT. Successful completion of this project will result in optimized imaging parameters for HP 129Xe diffusion MRI that will best detect and characterize lung microstructural changes in COPD. This will lay the foundation for future clinical trials to evaluate the potential of HP 129Xe diffusion MRI as a fundamentally improved approach for staging and monitoring progression of COPD.